Diabetic Neuropathies

OBJECTIVE-The purpose of this study was to determine the efficacy of anodyne monochromatic infrared photo energy (MIRE) in-home treatments over a 90-day period to improve peripheral sensation and self-reported quality of life in individuals with diabetes. RESEARCH DESIGN AND METHODS-This was a double-blind, randomized, sham-controlled clinical trail. We randomly assigned 69 individuals with diabetes and a vibration perception threshold (VPT) between 20 and 45 V to two treatment groups: active or sham treatment. Sixty patients (120 limbs) completed the study. Anodyne units were used at home every day for 40 min for 90 days. We evaluated nerve conduction velocities, VPT, Semmes-Weinstein monofilaments (SWM) (4-, 10-, 26-, and 60-g monofilaments), the Michigan Neuropathy Screening Instrument (MNSI), a 10-cm visual analog pain scale, and a neuropathyspecific quality of life instrument. We used a nested repeated-measures multiple ANOVA design. Two sites (great toe and fifth metatarsal) were tested on both the left and right feet of each patient, so two feet were nested within each patient and two sites were nested within each foot. To analyze the ordinal SWM scores, we used a nonparametric factorial analysis for longitudinal data. RESULTS-There were no significant differences in measures for quality of life, MNSI, VPT, SWM, or nerve conduction velocities in active or sham treatment groups (P Ͼ 0.05). CONCLUSIONS-Anodyne MIRE therapy was no more effective than sham therapy in the treatment of sensory neuropathy in individuals with diabetes.

The mechanisms underlying impairment of dynamic cerebral autoregulation in diabetes are not well known. Cardiovascular autonomic neuropathy (CAN) could contribute to dynamic cerebral autoregulation impairment. In this study, we assessed the association between CAN and impairment of dynamic cerebral autoregulation in patients with type 1 diabetes. Methods: We evaluated dynamic cerebral autoregulation (DCA) in patients with type 1 diabetes and no history of cerebrovascular disease. DCA was assessed with transcranial Doppler using the correlation coefficient index Mx method. Mx was calculated from slow changes in mean cerebral blood flow velocity and mean arterial blood pressure. Increase in Mx indicates weaker DCA, with a threshold for impaired DCA above 0.3. Moderate CAN was defined as reduced heart rate variability (HRV) on the following tests: deep controlled breathing, Valsalva maneuver or initiation of active standing. Severe CAN was defined as reduced HRV associated with orthostatic hypotension. Results: 60 patients were included (M/F: 33/27; mean age ± SD: 46 years ± 11.5). 23 patients had moderate CAN and 15 patients severe CAN. DCA was impaired in 37 patients. CAN was associated with impaired DCA (p = 0.005). Impairment of DCA was more pronounced in patients with severe CAN (p = 0.019). Glycosylated haemoglobin (HbA1c) was associated with impaired DCA in univariate analysis (p = 0.05). In multivariate analysis, only CAN was associated with impaired DCA (p = 0.007) whereas HbA1c was not (p = 0.161). Conclusions: CAN was associated with impaired DCA in type 1 diabetes. The magnitude of DCA impairment increased with the severity of CAN.

We evaluated the possible relation between plasma endothelin-1 (ET-1) levels and metabolic control, risk factors, treatment modalities, and diabetic microangiopathy, including nephropathy, neuropathy, and retinopathy in patients with Type 2 diabetes and healthy control group. Sixty-eight (39 females and 29 males) patients with Type 2 diabetes and 14 (6 females and 8 males) healthy subjects were included in the study. Plasma ET-1 levels were found to be 10.46 1.24 pmol/l in the diabetic group, whereas 7.97 0.41 pmol/l in the control group, which was statistically significant ( P < .01). We also found elevated plasma ET-1 levels in patients with the least one microvascular complication when compared with the uncomplicated diabetes group ( P = .02). Moreover, plasma ET-1 levels of the uncomplicated group was higher than the control group ( P < .05). Plasma ET-1 levels were significantly elevated in hypertensive diabetics than normotensive diabetics (t = 2.58, P = .012). It was also found to be elevated in diabetic patients with diabetes duration of more than 10 years when compared with patients less than 10 years ( P = .02). These findings can be interpreted as the increased damage of microvascular complications in the disease process that may lead to elevated ET-1 levels. Mean plasma ET-1 levels in diabetic patients with a family history of diabetes was found to be higher than patients with no family history of diabetes. Genetical and environmental factors may have an effect on ET-1 level. We also studied the correlations of plasma ET-1 levels on age, sex, fasting blood glucose levels, treatment modalities HbA1c, hyperlipidemia, C-peptide, Body Mass Index, and smoking, but did not find any statistically significant difference. In conclusion, plasma ET-1 levels are well correlated with microangiopathy, hypertension, increased disease duration, and family history of diabetes, but poorly correlated with metabolic control, treatment modalities, age, sex, hyperlipidemia, obesity, and smoking. D

Aim of study: Since the leaves of olive have been recommended in the literature as a remedy for the treatment of diabetes and they also contain antioxidant agents, we decided to investigate the possible effects of olive leaf extract (OLE) on in vitro and in vivo models of diabetic pain neuropathy. Materials and methods: The high glucose-induced cell damage in naive and NGF-treated Pheochromocytoma (PC12) cells and streptozotocin-induced diabetic rats were used. Tail-flick test was used to access nociceptive threshold. Cell viability was determined by MTT assay. Biochemical markers of neural apoptosis were evaluated using immunoblotting. Results: We found that elevation of glucose (4 times of normal) sequentially increases functional cell damage and caspase-3 activation in NGF-treated PC12 cells. Incubation of cells with OLE (200, 400 and 600 g/ml) decreased cell damage. Furthermore, the diabetic rats developed neuropathic pain which was evident from decreased tail-flick latency (thermal hyperalgesia). Activated caspase 3 and Bax/Bcl2 ratio were significantly increased in spinal cord of diabetic animals. OLE treatment (300 and 500 mg/kg per day) ameliorated hyperalgesia, inhibited caspase 3 activation and decreased Bax/Bcl2 ratio. Furthermore, OLE exhibited potent DPPH free radical scavenging capacity. Conclusion: The results suggest that olive leaf extract inhibits high glucose-induced neural damage and suppresses diabetes-induced thermal hyperalgesia. The mechanisms of these effects may be due, at least in part, to reduce neuronal apoptosis and suggest therapeutic potential of olive leaf extract in attenuation of diabetic neuropathic pain.

This study was designed to determine whether the relationship of glycated haemoglobin to diabetic microvascular complications shows any natural thresholds that could be useful in diagnosing diabetes. We examined a population-based sample of 3,190 Malay adults aged 40-80 years in Singapore. The microvascular outcomes of interest were: (1) any retinopathy, defined from fundus photographs; (2) mild retinopathy, defined as in (1); (3) moderate retinopathy, defined as in (1); (4) chronic kidney disease, defined from estimated glomerular filtration rate; (5) micro- or macroalbuminuria, defined from urinary albumin to creatinine ratio; and (6) peripheral neuropathy, defined from neurothesiometer or monofilament sensory testing. Increasing HbA(1c) was associated with all microvascular complications. The optimal cut-off points for detecting mild and moderate retinopathy were 6.6% (87.0% sensitivity, 77.1% specificity and area under the receiver operating characteristics [ROC] curve 0.899) an...

Background: The anticonvulsants pregabalin and gabapentin are both indicated for the treatment of peripheral neuropathic pain. The decision on which treatment provides the best alternative, should take into account all aspects of costs and outcomes associated with the two therapeutic options. The objective of this study was to examine the costeffectiveness of the two agents in the management of patients with painful diabetic neuropathy or postherpetic neuralgia, under the third party payer perspective in Greece.

There are substantial advances in understanding disordered gastrointestinal autonomic dysfunction in diabetes. It occurs frequently. The underlying pathogenesis is complex involving defects in multiple interacting cell types of the myenteric plexus as well. These defects may be irreversible or reversible. Gastrointestinal symptoms represent a major and generally underestimated source of morbidity for escalating health care costs in diabetes. Acute changes in glycaemia are both determinants and consequences of altered gastrointestinal motility. 35-90% of diabetic men have moderate-to-severe erectile dysfunction (ED). ED shares common risk factors with CVD. Diagnosis is based on medical/sexual history, including validated questionnaires. Physical examination and laboratory testing must be tailored to patient's complaints and risk factors. Treatment is based on PDE5-inhibitors (PDE5-I). Other explorations may be useful in patients who do not respond to PDE5-I. Patients at high cardiovascular risk should be stabilized by their cardiologists before sexual activity is considered or ED treatment is recommended. Estimates on bladder dysfunction prevalence are 43-87% of type 1 and 25% of type 2 diabetic patients, respectively. Common symptoms include dysuria, frequency, urgency, nocturia and incomplete bladder emptying. Diagnosis should use validated questionnaire for lower urinary tract symptoms. The type of bladder dysfunction is readily characterized with complete urodynamic testing. Sudomotor dysfunction is a cause of dry skin and is associated with foot ulcerations. Sudomotor function can be assessed by thermoregulatory sweat testing, quantitative sudomotor axon reflex test, sympathetic skin response, quantitative direct/indirect axon reflex testing and the indicator plaster.

With the aim to assess the prevalence and the main clinical correlations of skin lesions in diabetes mellitus, 457 diabetic subjects consecutively attending an outpatient clinic underwent a dermatological examination. Neurovascular foot lesions were excluded. Thirty-five of 64 IDDM patients (54%) had skin alterations mainly consisting of vitiligo (9% of all patients), psoriasis (9%) and eczema (8%). The most frequent skin lesions observed in 240/393 NIDDM subjects (61%) were represented by infections (20% of all patients) and diabetic dermopathy (12.5%), while other lesions were not common. NIDDM patients with skin infections had a worse metabolic control, and those with diabetic dermopathy had a greater prevalence of neuropathy and large vessel disease than patients without skin lesions. These data show that the prevalence of skin diseases in a large, unselected diabetic population is higher than expected and indicate that, in most cases, a careful dermatological examination and a better metabolic control are needed in order to improve quality of life in these patients.

Neuropathic pain is one of the most common complications of diabetes mellitus. As efficacy and tolerability of current therapy for neuropathic pain are not ideal, we need to develop the novel drug for better treatment. Curcumin as a natural flavonoid from Curcuma longa has considerable effects on nervous system such as, antidepressant, antinociceptive and neuroprotective effects. The present study was designed to investigate the effect of curcumin on diabetic peripheral neuropathic pain and possible involvement of opioid system. A single dose of 60 mg/kg streptozotocin was injected intraperitoneally to induce diabetes in rats. STZ-induced diabetic rats were treated with curcumin (50 mg/kg/day) acute and chronically. Thermal hyperalgesia and mechanical allodynia were measured on the days 0, 7, 14 and 21 after diabetes induction as behavioral scores of neuropathic pain. Chronic, but not acute, treatment with curcumin prevents the weight loss and attenuates mechanical allodynia in STZ-induced diabetic rats. Pretreatment with naloxone (1 mg/kg) significantly reduced anti-allodynic effect of chronic curcumin in von Frey filament test. Our results suggest that curcumin can be considered as a new therapeutic potential for the treatment of diabetic neuropathic pain and the activation of opioid system may be involved in the antinociceptive effect of curcumin.

Aims: To assess peripheral neuropathy following a standardized foot examination protocol in a representative population-based cohort of subjects with type 2 diabetes. Methods: In a geographically defined population, aged 40-70 years with diabetes prevalence of 3.5% according to medical records, we investigated 156 type 2 diabetic subjects, 95% Caucasian, mean age 61.7±7.2 years, duration of diabetes 7.0±5.7 years, and HbA 1c 7.3 ±2.4% (6.4% Mono-S), by questionnaires, clinical examinations, blood sampling, and review of medical records. Foot examination included clinical signs of peripheral neuropathy and tests of sensibility with monofilament, tuning fork, and assessments of the vibration perception thresholds (VPT). Results: Peripheral autonomic neuropathy (PAN) as judged by two or more signs of dysfunction was the most common and affected 43%. The prevalence of peripheral sensory neuropathy (PSN) was 15% by monofilament, 24% by tuning fork, and 28% by VPT expressed as ZscoreVPT ≥2.0 S.D. Twenty-nine percent had a VPT ≥25 V. Signs of peripheral motor neuropathy (PMN) affected 15%. Peripheral neuropathy, at least one variable, affected 67%, whereas 25% were affected by more than one variable of neuropathy, i.e., polyneuropathy. Exclusion of other identified causes for neuropathy than diabetes reduced the prevalence of diabetic polyneuropathy to 23%. Concurrent diabetic complications were 29% for retinopathy, 14% for incipient nephropathy, and 8% for overt nephropathy. The prevalence of macrovascular complications was 62% for CVD, 26% for PVD, and 11% for cerebrovascular lesion (CVL). Conclusion: Peripheral neuropathy was common in this representative type 2 diabetes population. Clinical signs of PAN were the most frequent followed by diminished perception of vibration and touch.

Diabetic neuropathy is associated with neurotrophic ulcerations of the skin and cornea. Decreased corneal sensitivity and impaired innervation lead to weakened epithelial wound healing predisposing patients to ocular complications such as corneal infections, stromal opacification, and surface irregularity. This review presents recent findings on impaired corneal innervation in diabetic individuals, and the findings suggest that corneal neuropathy might be an early indicator of diabetic neuropathy. Additionally, the recent findings for neuroprotective and regenerative therapy for diabetic keratopathy are presented.

p r i m a r y c a r e d i a b e t e s 8 ( 2 0 1 4 ) 65-69 Type 1 diabetes Foot complications Primary care a b s t r a c t Introduction: Painful peripheral neuropathy in people with type 1 diabetes is a disabling and costly complication. A greater understanding of predisposing factors and prescribing may facilitate more effective resource allocation.

Skin biopsies have primarily been used to study the non-myelinated nerve fibers of the epidermis in a variety of neuropathies. In the present study, we have expanded the skin biopsy technique to glabrous, non-hairy skin to evaluate myelinated nerve fibers in the most highly prevalent peripheral nerve disease, diabetic polyneuropathy (DPN). Twenty patients with DPN (Type I, n=9; Type II, n=11) and sixteen age-matched healthy controls (ages 29-73) underwent skin biopsy of the index finger, nerve conduction studies, and composite neuropathy scoring. In patients with DPN, we found a statistically significant reduction of both mechanoreceptive Meissner corpuscles (MC) and their afferent myelinated nerve fibers (p=0.01). This myelinated nerve fiber loss was correlated with the decreased amplitudes of sensory/motor responses in nerve conduction studies. This study supports the utilization of skin biopsy to quantitatively evaluate axonal loss of myelinated nerve fibers in patients with DPN.

Objective: Early detection of Diabetic Autonomic Neuropathy (DAN) could help prevent serious complications and mortality associated with this condition in type 2 diabetes. We aimed to determine the prevalence of Sudomotor Autonomic Dysfunction, Cardiac Autonomic Dysfunction
(SAD, CAD) in the early stages of glucose metabolism alterations, ranging from risk categories for type 2 diabetes (prediabetes) to recently established type 2 diabetes.
Research Design and Methods: It is a longitudinal, prospective and observational study (population consisting in 30 control subjects, 30 patients with increased risk for type 2 diabetes and 30 patients with type 2 diabetes ≤8 years of evolution. Study was carried out by designing a
modified battery of Ewing. To study autonomic: resting Heart Rate (HR), deep inspiration, controlled breathing, 30/15, Valsalva maneuver, Sustained handgrip test (SHGT) and prolonged QTc indexes) and to study sudomotor: measurement of the Skin Conductance Response (SCR) deep inspiration, controlled breathing, standing to orthostasis, Valsalva maneuver and SHGT. The ECG and the Electrodermal response signal (EDR) was recorded while the patients execute the tests.
Results: Results were statistically analyzed by taking into account the group the patients belonged to, their anthropometric variables (directly measured) and their results from blood tests. Obtained results allowed us to determine the order in which every autonomic index passes from
normal to abnormal and the corresponding nerve fibers involved.
Cardiac autonomic variables: resting HR: it is average value increases as the dysglicaemia progressed, significant differences were only found between the control and the type 2 diabetes group (p=0.041). Deep inspiration index: significant differences were only found between the
increased risk group and the type 2 diabetes group (p=0.047). 42.9% of the control subjects, 39.1% of the increased risk patients and 59.3% of type 2 diabetes presented anomalous values for this index.
Controlled breathing rate: significant differences were only found between thecontrol group and the type 2 diabetes group (p=0.008). 7.1% of the control subjects, 31.8% of the increased risk patients and
34.6% of type 2 diabetes presented anomalous values for this index.
Significant differences were only found between the control
group and the increased risk group (p=0.023).
Sudomotor autonomic variables: no significant differences were found between the groups for the average value of SCR, or anomalous values of SCR to the various autonomic stimuli studied. SCR-HR: we found significant correlation between the sudomotor response generated by the SHGT maneuver and the variation of the HR generated by this autonomic stimulus (p=0.036); not so for the remaining stimuli.
Conclusions: CAD appears to be the first manifestation of DAN
and is already present in prediabetes and short evolution type 2 diabetes. This finding suggests an early impairment of  arasympathetic fibers in disglycemic patients, and may help design preventive strategies aimed to avoid the severe complications related to this entity.

Report weight change baseline up to 12-15 months in duloxetine-treated patients during clinical trials of chronic painful conditions of diabetic peripheral neuropathic pain (DPNP), fibromyalgia, chronic low back pain (CLBP) and chronic knee pain as a result of osteoarthritis. Methods: Weight change data from 16 duloxetine studies in chronic painful conditions were pooled by pain condition and duration, creating 10 datasets. Datasets included placebo-controlled, open-label and routine-care-controlled designs. Assessments included mean weight change from baseline, baseline body mass index category, potentially clinically significant (PCS) weight change and weight-related treatment-emergent adverse events. Results: Total number of patients was 5111 with mean baseline weight ranging from 70 to 97 kg. All duloxetine groups had significant mean weight loss compared with placebo at acute phase completion (p £ 0.001). In studies > 3 months, patients from fibromyalgia and CLBP studies had overall mean weight increase (up to 1.1 kg), whereas patients in DPNP studies had overall mean weight loss ()0.33 to)1.7 kg) at end-point. Overall, the percentage of patients with PCS weight gain was 0.4-16% and PCS weight loss was 2.5-9.9%. Discussion: Weight change data in clinical trials of patients with fibromyalgia or CLBP treated with duloxetine for up to 15 months were consistent with data reported in 10 clinical trials of patients with major depressive disorder (MDD) using duloxetine up to 52 weeks. Patients with DPNP had weight loss at end-point. Conclusion: Mean weight changes and percentages of patients with PCS weight loss and weight gain observed in DPNP, fibromyalgia and CLBP with long-term duloxetine treatment were consistent with those reported previously for MDD studies. What's known A prior publication reported weight changes with long-term use (up to 52 weeks) of duloxetine in patients with major depressive disorder. What's new This manuscript extends those observations to report weight change with duloxetine use in clinical trials lasting up to 15 months in patients with chronic painful conditions.

Chronic pain can be considered as a highly salient stimulus that continuously taxes the attentional and salience processing networks, thus interfering with cognitive abilities and, more specifically, consuming attentional resources. The aim of the paper was to explore whether and how diabetic neuropathic pain (NP) affects attentional networks. We sought to achieve this by investigating resting state functional connectivity (rsFC) in diabetic NP patients and comparing it with that of matched healthy controls. NP patients showed a widespread reduction of connectivity in both the dorsal and ventral attentional networks, as well as in the dorsal anterior cingulated cortex (ACC), typically implicated in salience processing. We also found a generalized reduction of the length of functional connections in the NP group: in all the examined networks, the Euclidian distance between connected voxels was significantly shorter in patients vs. controls. In sum, our work showed that in diabetic NP pain a parieto-fronto-cingulate network controlling attention to external stimuli is impaired. In line with previous studies, we conclude that chronic pain can disrupt the synchrony of a common pool of brain areas, involved in self monitoring, pain processing and salience detection.

Diabetes mellitus with the mitochondrial DNA 3243(A–G) mutation is reported to represent 0.5–2.8% of the general diabetic population. Since the characterization of diabetes with the mutation is still incomplete, we undertook a nation-wide case-finding study of genetically defined ...

We investigated how postural responses to galvanic vestibular stimulation were affected by standing on a translating support surface and by somatosensory loss due to diabetic neuropathy. We tested the hypothesis that an unstable surface and somatosensory loss can result in an increase of vestibulospinal sensitivity. Bipolar galvanic vestibular stimulation was applied to subjects who were standing on a force platform, either on a hard, stationary surface or during a backward platform translation (9 cm, 4.2 cm/s). The intensity of the galvanic stimulus was varied from 0.25 to 1 mA. The amplitude of the peak body CoP displacement in response to the galvanic stimulus was plotted as a function of stimulus intensity for each individual. A larger increase in CoP displacement to a given increase in galvanic current was interpreted as an increase of vestibulospinal sensitivity. Subjects with somatosensory loss in the feet due to diabetes showed higher vestibulospinal sensitivity than healthy...

Patients with neuropathic pain syndromes are heterogeneous. They present with a variety of sensory symptoms and pain qualities. The knowledge of these data and etiology-specific differences is important to optimize clinical trial design and to develop more effective drugs. This investigation uses epidemiological and clinical data on the symptomatology of 2100 patients with painful diabetic neuropathy (DPN) and postherpetic neuralgia (PHN) from a cross-sectional survey (painDETECT) to (1) describe characteristic epidemiological differences, (2) analyse typical patterns of sensory symptoms in both cohorts and (3) determine whether questionnaires can capture these characteristics. PHN patients suffer more often from clinically relevant sensory disturbances although the average pain intensity is only marginally higher. This difference is particularly obvious with dynamic mechanical allodynia which is present in half of the PHN patients and in 18% of the DPN patients. Thermal hyperalgesi...

Background: Peripheral neuropathy is a common complication of diabetes mellitus. It has been shown that hyperglycemia may contribute to its development but the exact pathophysiology underlying this complication is not fully understood. Since oral magnesium supplementation can normalize hyperglycemia induced by diabetes in rats, this study was designed to examine the effect of oral magnesium administration on thermal hyperalgesia in streptozocin-induced diabetic rats. Material and methods: Twenty-four male adult wistar rats were divided equally into control, magnesium-treated control, diabetic and magnesium-treated diabetic groups. In magnesium-treated diabetic rats, magnesium sulfate (10 g/l) was added into the drinking water once diabetes was established (10 days after STZ injection) and continued for 8 weeks. Mg-treated control animals received magnesium sulfate in the same dose and over the same time period. The other two groups; control and diabetic animals, only received tap water. At the end of the 8 weeks, thermal pain threshold was assessed by tail flick test and magnesium and glucose plasma levels were measured in all groups. Result: A significant decrease ( p < 0.001) in thermal pain threshold and plasma magnesium levels and an increase in plasma glucose levels ( p < 0.001) were seen in diabetic rats 8 weeks after diabetes induction. After 8 weeks of oral magnesium, thermal hyperalgesia was normalized and plasma magnesium and glucose levels were restored towards normal. Conclusion: It is concluded that oral magnesium administration given at the time of diabetes induction may be able to restore thermal hyperalgesia, magnesium deficiency and hyperglycemia and in diabetic rats. #

A 51-year-old ASA physical status II, non-insulin-dependent diabetic male patient manifested lower limb nerve injury after receiving postoperative epidural analgesia with ropivacaine 0.2%. The case is presented, including a discussion of the relation between local anesthetic toxicity and diabetic neuropathy.

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independ...

AIM: To investigate the effect of Ginkgo biloba extract on the enteric neurons in the small intestine of diabetic rats. METHODS: Fifteen Wistar rats were divided into three groups: control group (C), diabetic group (D) and diabetic-treated (DT) daily with EGb 761 extract (50 mg/kg body weight) for 120 d. The enteric neurons were identified by the myosin-V immunohistochemical technique. The neuronal density and the cell body area were also analyzed. RESULTS: There was a significant decrease in the neuronal population (myenteric plexus P = 0.0351; submucous plexus P = 0.0217) in both plexuses of the jejunum in group D when compared to group C. With regard to the ileum, there was a significant decrease (P = 0.0117) only in the myenteric plexus. The DT group showed preservation of the neuronal population in the jejunum submucous plexus and in the myenteric plexus in the ileum. The cell body area in group D increased significantly (P = 0.0001) in the myenteric plexus of both segments studied as well as in the ileum submucosal plexus, when compared to C. The treatment reduced (P = 0.0001) the cell body area of the submucosal neurons of both segments and the jejunum myenteric neurons. CONCLUSION: The purified Ginkgo biloba extract has a neuroprotective effect on the jejunum submucous plexus and the myenteric plexus of the ileum of diabetic rats.

Background: To estimate the prevalence and risk factors of peripheral neuropathy (PN) in people with type 2 diabetes mellitus. Methods: 810 patients with type 2 diabetes (289 male and 521 female) from Isfahan Endocrinology and Metabolism Research Centre outpatient clinics, Iran , were examined. Part of the examination included an assessment of neurological function including neuropathic symptoms and physical signs, and nerve conduction velocity. Results: The prevalence of PN was 75.1% (95% confidence interval (CI) 72.1, 78.0). Peripheral neuropathy was associated with age, proteinuria, and duration of diabetes, insulin-treatment, and presence of retinopathy and ischaemic heart disease (IHD). The age-adjusted prevalence rate of PN was 78% higher among patients with IHD, 64% higher among patients with any retinopathy, 66% higher among insulin-treated type 2 diabetes, and greater with duration of diabetes. Using a stepwise binary logistic regression model, age, duration of diabetes and proteinuria were significant independent predictors of PN. Conclusion: PN is a common complication in this population of Iranian type 2 diabetic patients. It increases with age, duration of diabetes and proteinuria.

Purpose.To compare tear film metrics in patients with type 1 diabetes mellitus (DM) and healthy controls and investigate the association between peripheral neuropathy and ocular surface quality.Methods.Dry eye symptoms were quantified in 53 patients with type 1 DM and 40 age-matched controls. Ocular examination included tear film lipid layer thickness grading, tear film stability and quantity measurement, and retinal photography. DM individuals additionally underwent a detailed neuropathy assessment.Results.Neither mean age nor dry eye symptom scores differed significantly between the DM and control groups (P=0.12andP=0.33, resp.). Tear lipid thickness (P=0.02), stability (P&lt;0.0001), and quantity (P=0.01) were significantly lower in the DM group. Corneal sensitivity was also reduced in the DM group (P&lt;0.001) and tear film stability was inversely associated with total neuropathy score (r=-0.29,P=0.03).Conclusion.The DM group exhibited significantly reduced tear film stability, ...

In this study we investigated the agewise distributions of serum IgA concentrations in 1251 type 1 and 2224 type 2 diabetic patients, and the association between serum IgA concentration and diabetic complications (retinopathy, neuropathy, nephropathy, macroangiopathy, and hypertension). The IgA concentrations of all groups of diabetic patients were significantly higher than those of the corresponding subgroups of 943 control subjects, except for type 1 patients &gt;60 years of age. High IgA concentrations were found in 23.1% of the whole diabetic group. The prevalence of high IgA was significantly greater in males than in females among type 1 patients (24.4% vs 18%). In conclusion, an increase in circulating IgA concentrations is a generalized phenomenon among diabetic patients; IgA concentrations above the reference range are more common among male than female diabetics; and diabetic complications are associated with a significant increase in serum IgA concentration.

Background: Diabetic polyneuropathy (DPN) is one of the most common complications of diabetes and can exist with or without neuropathic pain. We were interested in how neuropathic pain impairs the quality of life in diabetic patients and what is the role of comorbidities in this condition. Methods: The study included 80 patients with painful DPN (group "P") and 80 patients with DPN, but without neuropathic pain (group "D"). Visual analogue scale (VAS) and Leeds assessment of neuropathic symptoms and signs (LANSS) pain scale were used for assessment of neuropathic pain, SF-36 standardized questionnaire for assessment of the quality of life and BDI questionnaire for assessment of depression. Results: Subjects in group P had statistically significantly lower values compared to group D in all 8 dimensions and both summary values of the SF-36 scale. We ascribe the extremely low results of all parameters of SF-36 scale in group P to painful diabetic polyneuropathy with its complications. The patients in group D showed higher average values in all dimension compared to group P, but also somewhat higher quality of life compared to general population of Croatia in 4 of 8 dimensions, namely vitality (VT), social functioning (SF), role-emotional (RE) and mental health (MH), which was unexpected result. Clinically, the most pronounced differences between two groups were noted in sleeping disorders and problems regarding micturition and defecation , which were significantly more expressed in group P. The similar situation was with walking distance and color-doppler sonography of carotid arteries, which were significantly worse in group P. Consequently, subjects in group P were more medicated than the patients in group D, particularly with tramadol, antiepileptics and antidepressants. Conclusion: Painful DPN is a major factor that influences various aspects of quality of life in diabetic patients. Additionally, this study gives an overview of diabetic population in the Republic of Croatia, information that could prove useful in future studies.

The objective of this study was to compare the efficacy and tolerability of gabapentin and amitriptyline monotherapy in painful diabetic neuropathy. This was a 12-week, open-label, prospective, randomized trial. Twenty-five type-II diabetic patients with pain attributed to diabetic neuropathy and a minimum score of 2 on a pain intensity scale ranging from 0 (no pain) to 4 (excruciating pain) were randomized to receive either gabapentin, titrated from 1,200 mg/day to a maximum of 2,400 mg/day, or amitriptyline, titrated from 30 mg/day to a maximum of 90 mg/day. Both drugs were titrated over a 4-week period and maintained at the maximum tolerated dose for 8 weeks. The main outcome measures were weekly pain intensity and paresthesia intensity, measured on two categorical scales. Thirteen patients received gabapentin and 12 received amitriptyline. All 25 patients completed the trial. Gabapentin produced greater pain reductions than amitriptyline (mean final scores were 1.9 vs. 1.3 points below baseline scores; P = 0.026). Decreases in paresthesia scores also were in favor of gabapentin (1.8 vs. 0.9 points; P = 0. 004). Adverse events were more frequent in the amitriptyline group than in the gabapentin group: they were reported by 11/12 (92%) and 4/13 (31%) of patients, respectively (P = 0.003). Side effects were the main limiting factor preventing dose escalation. Gabapentin produced greater improvements than amitriptyline in pain and paresthesia associated with diabetic neuropathy. Additionally, gabapentin was better tolerated than amitriptyline. Further controlled trials are needed to confirm these preliminary results.

Background: There is evidence that diabetic polyneuropathy (PNP) is associated with reduced bone mineral density (BMD) in type 1 diabetes but little is known about the impact of diabetic PNP on bone metabolism in type 2 diabetes. Objectives: The aim of this study was to evaluate differences in bone metabolism by measuring markers of bone turnover and BMD in men and postmenopausal women with type 2 diabetes and diabetic PNP compared with those without PNP. Gender differences were analyzed for both groups of patients. Methods: One hundred twenty patients with type 2 diabetes, 68 without PNP (43 men, 25 women, mean age 62 [8] years) and 52 with PNP (28 men, 24 women, mean age 64 [8] years) were studied. Clinical parameters with bone turnover biomarkers such as osteocalcin, bone alkaline phosphatase, procollagen type 1 amino-terminal propeptide, and carboxy-terminal telopeptide of type 1 collagen were measured in all patients. Dual energy x-ray absorptiometry to evaluate BMD was performed in a subgroup of patients. Results: After controlling for age, body mass index, duration of diabetes, smoking, glycosylated hemoglobin, homeostasis model assessment index for insulin resistance, serum C-reactive protein, creatinine, calcium, gamma-glutamyltransferase, parathyroid and sex hormones levels, presence of micro/macrovascular complications, statin-as well as diabetes-related therapies, levels of carboxy-terminal telopeptide of type 1 collagen and procollagen type 1 amino-terminal propeptide were significantly higher among patients with PNP when compared with patients without PNP (P ϭ 0.01 and P ϭ 0.03, respectively). Differences in bone biomarkers were more pronounced among men with diabetes. BMD did not differ significantly between patients with and without PNP, independent of gender. Conclusions: Male patients with PNP exhibit a higher rate of bone turnover than men without PNP. High rate of bone turnover increases the susceptibility for developing osteoporosis. Prevention of diabetic PNP might also reduce the incidence of osteoporosis and fractures in patients with type 2 diabetes. (Gend Med.

Recent data indicate that T-type Ca 2ϩ channels are amplifiers of peripheral pain signals, but their involvement in disorders of sensory neurons such as those associated with diabetes is poorly understood. To address this issue, we used a combination of behavioral, immunohistological, molecular, and electrophysiological studies in rats with streptozotocin (N-[methylnitrosocarbamoil]-Dglucosamine)-induced early diabetic neuropathy. We found that, in parallel with the development of diabetes-induced pain, T-type current density increased by twofold in medium-size cells from L 4-L 5 dorsal root ganglia (DRG) with a depolarizing shift in steady-state inactivation. This not only correlated closely with more prominent afterdepolarizing potentials (ADPs) but also increased cellular excitability manifested as a lower threshold for burst firing in diabetic than in control cells. T-type currents and ADPs were potently inhibited by nickel and enhanced by L-cysteine, suggesting that the Ca V 3.2 T-type channel isoform was upregulated. Both control and diabetic DRG cells with ADPs stained positively for isolectin B 4 , but only diabetic cells responded robustly to capsaicin, suggesting enhanced nociceptive function. Because increased excitability of sensory neurons may result in such pathological perceptions of pain as hyperalgesia and allodynia, upregulation of T-type Ca 2ϩ currents and enhanced Ca 2ϩ entry into these cells could contribute to the development of symptoms in diabetic neuropathy.

This study determined if deficits in corneal nerve fiber length (CNFL) assessed using corneal confocal microscopy (CCM) can predict future onset of diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS CNFL and a range of other baseline measures were compared between 90 nonneuropathic patients with type 1 diabetes who did or did not develop DPN after 4 years. The receiver operator characteristic (ROC) curve was used to determine the capability of single and combined measures of neuropathy to predict DPN. RESULTS DPN developed in 16 participants (18%) after 4 years. Factors predictive of 4-year incident DPN were lower CNFL (P = 0.041); longer duration of diabetes (P = 0.002); higher triglycerides (P = 0.023); retinopathy (higher on the Early Treatment of Diabetic Retinopathy Study scale) (P = 0.008); nephropathy (higher albumin-tocreatinine ratio) (P = 0.001); higher neuropathy disability score (P = 0.037); lower cold sensation (P = 0.001) and cold pain (P = 0.027) thresholds; higher warm sensation (P = 0.008), warm pain (P = 0.024), and vibration (P = 0.003) thresholds; impaired monofilament response (P = 0.003); and slower peroneal (P = 0.013) and sural (P = 0.002) nerve conduction velocity. CCM could predict the 4-year incident DPN with 63% sensitivity and 74% specificity for a CNFL threshold cutoff of 14.1 mm/mm 2 (area under ROC curve = 0.66, P = 0.041). Combining neuropathy measures did not improve predictive capability. CONCLUSIONS DPN can be predicted by various demographic, metabolic, and conventional neuropathy measures. The ability of CCM to predict DPN broadens the already impressive diagnostic capabilities of this novel ophthalmic marker. Diabetic peripheral neuropathy (DPN) can result in pain, foot ulceration, and lower extremity amputation (1). Unmyelinated nerve fibers can now be examined at approximately original magnification 3500 using a laser scanning corneal confocal microscope (CCM) to image the subbasal nerve plexus of the human cornea in vivo (2). This approach has been validated as a viable alternative for assessing DPN (3-5). Increased severity of DPN is associated with reduced corneal nerve fiber length (CNFL) (4,5) and corneal sensitivity (6,7), assessed using CCM and noncontact corneal esthesiometry (NCCE), respectively.

Apoptosis a b s t r a c t Aims: Hyperglycemia causes generation of free radicals which leads to oxidative stress and apoptosis in various cells. The present study was undertaken to investigate the correlation between oxidative stress and apoptotic markers in lymphocytes of diabetic patients with chronic non healing wounds.

The purpose of this study is to suggest a simple, new method of screening for diabetic neuropathy. We measured blood volume changes by photoplethysmography (PPG) and blood perfusion by laser Doppler (LD) in the index fingers and big toes in 40 control subjects and in 50 (19 mild, 17 moderate, and 14 severe based on the nerve conduction velocity (NCV) test) and 35 diabetic patients with and without neuropathy, respectively. According to the results of PPG and LD measurements, the toe to finger ratios obtained from the neuropathic group were significantly higher than those from the control (p \ 0.001) and the non-neuropathic groups (p \ 0.001). Based on the NCV, the sensitivity of the LD method (92.0%) was higher than that of the PPG method (84.0%) for both left and right sides. Although specificity of the LD (92.8%) was also higher than the PPG (84.3%) bilaterally, the PPG showed better reproducibility (5.5 versus 9.5%) and a significant ratio increase with severity, while the LD did not. Our suggested PPG method using the toe to finger ratio is reliable, simple, economical, and accurate, and could become an effective new screening tool for the early detection of diabetic neuropathy.

Background: Peripheral neuropathy is a common complication of diabetes mellitus. It has been shown that hyperglycemia may contribute to its development but the exact pathophysiology underlying this complication is not fully understood. Since oral magnesium supplementation can normalize hyperglycemia induced by diabetes in rats, this study was designed to examine the effect of oral magnesium administration on thermal hyperalgesia in streptozocin-induced diabetic rats. Material and methods: Twenty-four male adult wistar rats were divided equally into control, magnesium-treated control, diabetic and magnesium-treated diabetic groups. In magnesium-treated diabetic rats, magnesium sulfate (10 g/l) was added into the drinking water once diabetes was established (10 days after STZ injection) and continued for 8 weeks. Mg-treated control animals received magnesium sulfate in the same dose and over the same time period. The other two groups; control and diabetic animals, only received tap water. At the end of the 8 weeks, thermal pain threshold was assessed by tail flick test and magnesium and glucose plasma levels were measured in all groups. Result: A significant decrease ( p < 0.001) in thermal pain threshold and plasma magnesium levels and an increase in plasma glucose levels ( p < 0.001) were seen in diabetic rats 8 weeks after diabetes induction. After 8 weeks of oral magnesium, thermal hyperalgesia was normalized and plasma magnesium and glucose levels were restored towards normal. Conclusion: It is concluded that oral magnesium administration given at the time of diabetes induction may be able to restore thermal hyperalgesia, magnesium deficiency and hyperglycemia and in diabetic rats. #

Motor conduction velocities (CVs) were correlated with distal compound muscle action potential (CMAP) amplitudes for tibial, peroneal, and median nerves in patients with biopsy-proven chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic neuropathy, and amyotrophic lateral sclerosis. Only in the diabetic patients did CV significantly correlate with CMAP amplitude. The data show that diabetic neuropathy produces conduction velocity slowing that cannot be explained by axon loss alone, and that differentiation between diabetic neuropathy and CIDP in an individual nerve is difficult.

The effect of bromocriptine on intraocular pressure has been investigated in a group of 8 diabetic patients with autonomic neuropathy, to test the hypothesis that bromocriptine exerts its ocular hypotenisve action through presynaptic dopamine receptors. Bromocriptine eye drops (0.025%) produced a significant fall in intraocular pressure in a control group of 8 matched normal volunteers, but this effect was not seen in the eyes of the diabetic patients. These results are consistent with a presynaptic site of action of bromocriptine.

We sought to examine the changes in the strength-duration time constant (SDTC) of the median nerve in diabetic polyneuropathy. The SDTC is a measure of axonal excitability and depends on the biophysical properties of the axonal membrane. It may provide some information about Na + channel functioning. Forty-nine diabetic patients (30 men, 19 women; mean age, 54.6 AE 9.4 years) and 15 age-matched healthy subjects (11 men, 4 women; mean age, 53.1 AE 7.6 years) participated in the study. SDTC and rheobase values were 384.5 AE 97.9 ms and 4.6 AE 2.4 mA in patients and 313.8 AE 46.7 ms and 6.0 AE 2.6 mA in controls. The SDTC was found to be significantly different between the two groups (P = .009 for SDTC and P = .066 for rheobase). Fasting glucose and HbA1c levels of patients were 206.6 AE 88.7 mg/dL and 8.8 AE 2.4%, and these were not correlated with SDTC or rheobase (P < .05). We suggest that longer SDTC, indicating increased axonal excitability may develop in patients with polyneuropathy associated with uncontrolled diabetes.

Objective: Hyperventilation and ischaemia increase axonal excitability by changing Na + conductance in healthy subjects. However, the changes in excitability during and after ischaemia in diabetic patients are less than in healthy controls. This is known as ischaemic resistance. In this study, we investigated the effects of hyperventilation for 20 min on strength-duration time constant (SDTC) of motor axons of the median nerve of diabetic patients with polyneuropathy to determine whether diabetics are less affected by hyperventilation, a form of resistance similar to the ischaemic resistance of diabetics. Methods: The SDTC of 14 diabetic patients with polyneuropathy and 10 healthy volunteers were measured following stimulation of right median nerve at the wrist prior to and after hyperventilation for 20 min. Results: There was a significant increase in the SDTC in control subjects, but no significant change in the SDTC for patients with diabetic polyneuropathy. The score of the clinical response (paraesthesiae and carpopedal spasm) to hyperventilation of controls was also significantly greater in the controls than the patients. Conclusion: Hyperventilation for 20 min has little influence on SDTC in patients with diabetic polyneuropathy. Significance: The 'resistance' of diabetic nerve is not confined to ischaemia but involves other manoeuvres that can alter axonal excitability.

The pathophysiology of diabetes is multifactorial and no single etiology is at the forefront. The proposed mechanisms of erectile dysfunction (ED) in diabetic patients includes elevated advanced glycation end-products (AGEs) and increased levels of oxygen free radicals, impaired nitric oxide (NO) synthesis, increased endothelin B receptor binding sites and ultrastructural changes, upregulated RhoA/Rho-kinase pathway, NO-dependent selective nitrergic nerve degeneration and impaired cyclic guanosine monophosphate (cGMP)-dependent kinase-1 (PKG-1). The treatment of diabetic ED is multimodal. Treatment of the underlying hyperglycemia and comorbidities is of utmost importance to prevent or halt the progression of the disease. The peripherally acting oral phosphodiesterase type 5 (PDE5) inhibitors are the mainstay of oral medical treatment of ED in diabetics. Vacuum erection devices are an additional treatment as a non-invasive treatment option. Local administration of vasoactive medication via urethral suppository or intracorporal injection can be effective with minimal side-effects. Patients with irreversible damage of the erectile mechanism are candidates for penile implantation. Future strategies in the evolution of the treatment of ED are aimed at correcting or treating the underlying mechanisms of ED. With an appropriate vector, researchers have been able to transfect diabetic animals with agents such as neurotrophic factors and nitric oxide synthase (NOS). Further studies in gene therapy are needed to fully ascertain its safety and utility in humans.

Our goal was to assess the patient-level burden among subjects with painful diabetic peripheral neuropathy (DPN). Community-based physicians recruited patients with painful DPN (N = 255) between April and October 2003. Patients completed a survey on pain experience ( ...

Background: Early markers of diabetic autonomic neuropathy (DAN) in an electrocardiogram (ECG) include elevated R wave amplitudes, widening of QT c intervals and decreased heart rate variability (HRV). The severity of DAN has a direct relationship with mortality risk. Aerobic exercise training is a common recommendation for the delay and possible reversal of cardiac dysfunction. Limited research exists on ECG measures for the evaluation of aerobic exercise training in Zucker Diabetic Fatty (ZDF) rat, a model of type 2 diabetes. The objective of this study was to assess whether aerobic exercise training may attenuate diabetes induced ECG changes. Methods: Male ZDF (obese fa/fa) and control Zucker (lean fa/+) rats were assigned to 4 groups: sedentary control (SC), sedentary diabetic (SD), exercised control (EC) and exercised diabetic (ED). The exercised groups began 7 weeks of treadmill training after the development of diabetes in the ED group. Baseline (prior to the training) and termination measurements included body weight, heart weight, blood glucose and glycated hemoglobin levels and ECG parameters. One way repeated measures ANOVA (group) analyzed within and between subject differences and interactions. Pearson coefficients and descriptive statistics described variable relationships and animal characteristics. Results: Diabetes caused crucial changes in R wave amplitudes (p < 0.001), heart rate variability (p < 0.01), QT intervals (p < 0.001) and QT c intervals (p < 0.001). R wave amplitude augmentation in SD rats from baseline to termination was ameliorated by exercise, resulting in R wave amplitude changes in ED animals similar to control rats. Aerobic exercise training neither attenuated QT or QT c interval prolongation nor restored decreases in HRV in diabetic rats. Conclusion: This study revealed alterations in R wave amplitudes, HRV, QT and QT c intervals in ZDF rats. Of these changes, aerobic exercise training was able to correct R wave amplitude changes. In addition, exercise has beneficial effect in this diabetic rat model in regards to ECG correlates of left ventricular mass.

To assess the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in the management of chronic pain. METHODS: Randomized, controlled trials of SSRIs in the management of chronic pain were identified by searching MEDLINE from 1966 to 1997 and by contacting the manufacturers of SSRIs available in the United States. MAIN RESULTS: Nineteen studies were identified, including 10 on the treatment of headache, 3 on diabetic neuropathy, 3 on fibromyalgia, and 3 on mixed-chronic pain. SSRIs were consistently helpful for mixed-chronic pain. Results were conflicting for migraine headache, tension headache, diabetic neuropathy, and fibromyalgia. CONCLUSIONS: SSRIs appear to be beneficial for mixedchronic pain. It is unclear, from the available evidence, whether SSRIs are beneficial for migraine headaches, tension headaches, diabetic neuropathy, or fibromyalgia. For those patients it may be reasonable to reserve SSRIs for those who fail to respond to other medications or who are intolerant of their side effects.

Pain may be the most common reason patients seek treatment from physicians. When persistent and unrelieved, pain can frustrate both the person suffering with this condition and the physician trying to alleviate it. Relief from such discomfort may be particularly difficult to achieve and fraught with misconceptions. Treatment usually requires trials of physical, pharmacologic, and surgical interventions to achieve resolution. In cases that remain insoluble, patients must accept partial relief and seek adaptive strategies. Sources of persistent pain may be nociceptive or neuropathic. Both utilize the same nerve pathways for transmission, but significant physiologic differences exist in mechanisms through which these painful stimuli are biologically processed and resolved. Nociceptive pain resulting from a known or obvious source (eg, trauma, cancer metastasis, ischemia, arthritis) is often easy to identify. Neuropathic pain, however, may occur in the absence of an identifiable precipi...

Aim/hypothesisImmune mechanisms have been proposed to play a role in the development of diabetic neuropathy. We employed in vivo corneal confocal microscopy (CCM) to quantify the presence and density of Langerhans cells (LCs) in relation to the extent of corneal nerve damage in Bowman&#x27;s layer of the cornea in diabetic patients.

Aims: To reevaluate urodynamic findings of bladder dysfunction (BD) in type 2 diabetic patients with patient characteristics and concommittant chronic complications. Methods: Patients (M/F:27/27) with lower urinary tract symptoms (LUTS) underwent a detailed urodynamic investigation. Urodynamic findings were classified as diabetic cystopathy [DC, characterized by impaired bladder sensation, increased post-void residual urine (PVR) and increased bladder capacity and decreased bladder contractility], detrusor overactivity, bladder outlet obstruction (BOO), urge and stress urinary incontinence or BD in which one of the alterations was included. Glycated hemoglobin (HbA1C), diabetic retinopathy, nephropathy, sensorimotor, and autonomic neuropathies were evaluated. Results: BD was present in 74.07% of men (DC, 50%; BOO, 25%; detrusor overactivity, 25%) and in 59.26% of diabetic women (DC, 43.75%; detrusor overactivity, 31%; urge incontinence, 12.5%; stress urinary incontinence 12.5%). In men, age, duration of diabetes and HbA1C threshold values predicting BD were >64 years, >9 year, >7.9%, while in women, they were >56 years, >8 years, >7%, respectively. Prolongation of QTc, abnormal esophageal transit and gastric emptying times, diabetic retinopathy, and microalbuminuria were associated with an increased risk of PVR ! 100 ml. Conclusions: DC was the most frequent finding in patients. Ageing, duration of diabetes, worse metabolic control, PVR 100 ml, cardiac, esophageal and gastric parasympathetic autonomic neuropathies, retinopathy, and microalbuminuria provided a means to predict BD in patients in order to investigate by urodynamics. The establishment of DC in at least 8-9 years after the diagnosis of type 2 DM was an important parameter to inform our diabetic patients.

There are 22.3 million people in the United States with diabetes, of whom 15-25% are at risk for foot ulceration. Diabetic foot ulcers (DFUs) are a growing health problem. DFUs are a leading cause of infection, amputation, and hospitalization in patients with diabetes mellitus. Guidelines for the treatment of DFUs were published by the Wound Healing Society (WHS) in 2006. However, in the past few years new evidence has emerged that improves our understanding of previous recommendations. The objectives of the WHS DFU guidelines are to systematically evaluate the medical literature to assist clinicians in making health care decisions, identify areas that need additional research, and to clarify controversial diagnosis and treatment strategies. An advisory panel comprised of academicians, clinicians, researchers, and industry representatives was chosen to update the 2006 guidelines. CLIN S Clinical series RCT Randomized clinical trial LIT REV Literature review STAT Statistical analysis, meta-analysis, consensus CROSS S Cross sectional study RETRO S Retrospective series review GUIDELINES FOR THE DIAGNOSIS OF LOWER EXTREMITY DIABETIC ULCERS Preamble: Ulcers of the lower extremity may be caused by a variety of conditions, including neuropathy, ischemia, venous hypertension, and pressure. Patients with diabetes